EP0332109B1 - Dérivés d'acide phénoxyalkylcarboxylique et procédé pour leur préparation - Google Patents
Dérivés d'acide phénoxyalkylcarboxylique et procédé pour leur préparation Download PDFInfo
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- EP0332109B1 EP0332109B1 EP89103897A EP89103897A EP0332109B1 EP 0332109 B1 EP0332109 B1 EP 0332109B1 EP 89103897 A EP89103897 A EP 89103897A EP 89103897 A EP89103897 A EP 89103897A EP 0332109 B1 EP0332109 B1 EP 0332109B1
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- European Patent Office
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- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 12
- 239000002253 acid Substances 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 91
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 150000001447 alkali salts Chemical class 0.000 claims description 5
- 150000004677 hydrates Chemical class 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- -1 alkali metal cyanide Chemical class 0.000 claims description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 230000003266 anti-allergic effect Effects 0.000 claims 1
- 239000000043 antiallergic agent Substances 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 239000000203 mixture Substances 0.000 description 25
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 0 CC(c(ccc(S)c1*)c1O)=O Chemical compound CC(c(ccc(S)c1*)c1O)=O 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 229910010272 inorganic material Inorganic materials 0.000 description 5
- 239000011147 inorganic material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 208000026935 allergic disease Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- MOOJHHUMEBUKFQ-UHFFFAOYSA-N ethyl 4-(6-acetyl-2-propyl-3-sulfanylphenoxy)butanoate Chemical compound CCCC1=C(S)C=CC(C(C)=O)=C1OCCCC(=O)OCC MOOJHHUMEBUKFQ-UHFFFAOYSA-N 0.000 description 4
- OZKSBPMWKLECHO-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenyl)sulfanylpropoxy]-2-propylphenoxy]butanoate Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1SCCCOC1=CC=C(C(C)=O)C(OCCCC(=O)OCC)=C1CCC OZKSBPMWKLECHO-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 3
- 150000002617 leukotrienes Chemical class 0.000 description 3
- KNQROEPUZNODJT-UHFFFAOYSA-N 1-[4-(3-bromopropylsulfanyl)-2-hydroxy-3-propylphenyl]ethanone Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1SCCCBr KNQROEPUZNODJT-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- LDPSZWXLWFSOEA-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-(dimethylcarbamoylsulfanyl)-2-propylphenoxy]butanoate Chemical compound CCCC1=C(SC(=O)N(C)C)C=CC(C(C)=O)=C1OCCCC(=O)OCC LDPSZWXLWFSOEA-UHFFFAOYSA-N 0.000 description 2
- OWSPXVBXNJVKMV-UHFFFAOYSA-N ethyl 7-(6-acetyl-2-propyl-3-sulfanylphenoxy)heptanoate Chemical compound CCCC1=C(S)C=CC(C(C)=O)=C1OCCCCCCC(=O)OCC OWSPXVBXNJVKMV-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- RLDRJVCMMIXING-UHFFFAOYSA-N s-[4-acetyl-3-(6-bromohexoxy)-2-propylphenyl] n,n-dimethylcarbamothioate Chemical compound CCCC1=C(SC(=O)N(C)C)C=CC(C(C)=O)=C1OCCCCCCBr RLDRJVCMMIXING-UHFFFAOYSA-N 0.000 description 2
- XAVSBFFGZLJYMX-UHFFFAOYSA-N s-[4-acetyl-3-(6-cyanohexoxy)-2-propylphenyl] n,n-dimethylcarbamothioate Chemical compound CCCC1=C(SC(=O)N(C)C)C=CC(C(C)=O)=C1OCCCCCCC#N XAVSBFFGZLJYMX-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 description 1
- DRGBHKZRLWJAOU-UHFFFAOYSA-N 1-[4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl]ethanone Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1OCCCBr DRGBHKZRLWJAOU-UHFFFAOYSA-N 0.000 description 1
- FGIBVLDTDQWCBX-UHFFFAOYSA-N 1-[4-(3-bromopropylsulfinyl)-2-hydroxy-3-propylphenyl]ethanone Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1S(=O)CCCBr FGIBVLDTDQWCBX-UHFFFAOYSA-N 0.000 description 1
- ITEPNCQMHDEMOT-UHFFFAOYSA-N 1-[4-(3-bromopropylsulfonyl)-2-hydroxy-3-propylphenyl]ethanone Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1S(=O)(=O)CCCBr ITEPNCQMHDEMOT-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- KPWYNAGOBXLMSE-UHFFFAOYSA-N Tipelukast Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1SCCCOC1=CC=C(C(C)=O)C(OCCCC(O)=O)=C1CCC KPWYNAGOBXLMSE-UHFFFAOYSA-N 0.000 description 1
- CCUAACZBYBKMCM-UHFFFAOYSA-N [4-(dimethylcarbamoylsulfanyl)-2-hydroxy-3-propylphenyl] acetate Chemical compound CCCC1=C(O)C(OC(C)=O)=CC=C1SC(=O)N(C)C CCUAACZBYBKMCM-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000036428 airway hyperreactivity Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000004044 bronchoconstricting agent Substances 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 230000003435 bronchoconstrictive effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000439 effect on bronchoconstriction Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- MEFUYKDJCOTBGV-UHFFFAOYSA-N ethyl 4-(6-acetyl-3-hydroxy-2-propylphenoxy)butanoate Chemical compound CCCC1=C(O)C=CC(C(C)=O)=C1OCCCC(=O)OCC MEFUYKDJCOTBGV-UHFFFAOYSA-N 0.000 description 1
- HSQXDCYCCIHYEE-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-[2-(4-acetyl-3-hydroxy-2-propylphenyl)sulfanylethoxy]-2-propylphenoxy]butanoate Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1SCCOC1=CC=C(C(C)=O)C(OCCCC(=O)OCC)=C1CCC HSQXDCYCCIHYEE-UHFFFAOYSA-N 0.000 description 1
- DTUNTCQHRCHHRL-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfanyl]-2-propylphenoxy]butanoate Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1OCCCSC1=CC=C(C(C)=O)C(OCCCC(=O)OCC)=C1CCC DTUNTCQHRCHHRL-UHFFFAOYSA-N 0.000 description 1
- WIOSSTUSMBRDII-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfinyl]-2-propylphenoxy]butanoate Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1OCCCS(=O)C1=CC=C(C(C)=O)C(OCCCC(=O)OCC)=C1CCC WIOSSTUSMBRDII-UHFFFAOYSA-N 0.000 description 1
- NRQPIQGOUDCVQI-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]-2-propylphenoxy]butanoate Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1OCCCS(=O)(=O)C1=CC=C(C(C)=O)C(OCCCC(=O)OCC)=C1CCC NRQPIQGOUDCVQI-UHFFFAOYSA-N 0.000 description 1
- AZPABVZRKOJPQA-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenyl)sulfanylpropylsulfanyl]-2-propylphenoxy]butanoate Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1SCCCSC1=CC=C(C(C)=O)C(OCCCC(=O)OCC)=C1CCC AZPABVZRKOJPQA-UHFFFAOYSA-N 0.000 description 1
- DMDMMIAPHKJLPG-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenyl)sulfinylpropoxy]-2-propylphenoxy]butanoate Chemical compound C1=CC(C(C)=O)=C(OCCCC(=O)OCC)C(CCC)=C1OCCCS(=O)C1=CC=C(C(C)=O)C(O)=C1CCC DMDMMIAPHKJLPG-UHFFFAOYSA-N 0.000 description 1
- LHPYBOBOZCCPSW-UHFFFAOYSA-N ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenyl)sulfonylpropoxy]-2-propylphenoxy]butanoate Chemical compound C1=CC(C(C)=O)=C(OCCCC(=O)OCC)C(CCC)=C1OCCCS(=O)(=O)C1=CC=C(C(C)=O)C(O)=C1CCC LHPYBOBOZCCPSW-UHFFFAOYSA-N 0.000 description 1
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 1
- MHNRFQXYPYEZGF-UHFFFAOYSA-N ethyl 5-(6-acetyl-2-propyl-3-sulfanylphenoxy)pentanoate Chemical compound CCCC1=C(S)C=CC(C(C)=O)=C1OCCCCC(=O)OCC MHNRFQXYPYEZGF-UHFFFAOYSA-N 0.000 description 1
- RNTFFHREOZADGS-UHFFFAOYSA-N ethyl 6-(6-acetyl-2-propyl-3-sulfanylphenoxy)hexanoate Chemical compound CCCC1=C(S)C=CC(C(C)=O)=C1OCCCCCC(=O)OCC RNTFFHREOZADGS-UHFFFAOYSA-N 0.000 description 1
- OOMUIUPBVWMFRK-UHFFFAOYSA-N ethyl 9-(6-acetyl-2-propyl-3-sulfanylphenoxy)nonanoate Chemical compound CCCC1=C(S)C=CC(C(C)=O)=C1OCCCCCCCCC(=O)OCC OOMUIUPBVWMFRK-UHFFFAOYSA-N 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- TWNCYHSLYIINQX-UHFFFAOYSA-N s-(4-acetyl-3-hydroxy-2-propylphenyl) n,n-dimethylcarbamothioate Chemical compound CCCC1=C(SC(=O)N(C)C)C=CC(C(C)=O)=C1O TWNCYHSLYIINQX-UHFFFAOYSA-N 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
Definitions
- This invention is concerned with certain novel phenoxyalkylcarboxylic acid derivatives which have strong and selective leukotriene antagonist activity, and are useful for prevention and treatment of allergic diseases such as bronchial asthma and so on, their intermediates and their preparation processes thereof.
- Leukotrienes (leukotriene C 4 , D 4 , E 4 ), which are metabolites of arachidonic acid through 5'-lipoxygenase pathway, are constituents of SRS-A (slow reacting substance of anaphylaxis), being an important mediator of the immediate type allergic diseases such as bronchial asthma. Accordingly, the drugs which exert antagonis- ticeffects on leukotrienes are promising in the treatment of allergic diseases. But, only few drugs having those effects through the internal use are known and none is practically used.
- the compounds of the general formula (I) can be prepared on the hereinafter mentioned routes.
- this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide etc. under a reaction temperature of the room temperature to the solvent refluxing temperature.
- an organic solvent for example acetone, methylethylketone, diethylketone or dimethylformamide etc.
- an inorganic base for example potassium carbonate or sodium carbonate etc. and further the addition of potassium iodide are also recommendable.
- this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide etc. under a reaction temperature of the room temperature to the solvent refluxing temperature.
- an organic solvent for example acetone, methylethylketone, diethylketone or dimethylformamide etc.
- an inorganic base for example potassium carbonate or sodium carbonate etc. and further the addition of potassium iodide are also recommendable.
- this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide etc. under a reaction temperature of the room temperature to the solvent refluxing temperature.
- an inorganic base for example potassium carbonate or sodium carbonate and further the addition of potassium iodide are also recommendable.
- dimethylaminocarbonyl group or benzyl group etc. can be exemplified as the protective group for thiol group.
- this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide under a reaction temperature of the room temperature to the solvent refluxing temperature. Then, the compounds represented by the general formula (IX) are allowed to react with sodium cyanide or potassium cyanide to give compounds of the general formula (X). (wherein R 3 and n are as defined in the above)
- this reaction is conducted in an organic solvent, for example dimethyl sulfoxide or dimethylformamide under a temperature of the room temperature to 100°C.
- the compounds represented by the general formula (X) are subjected to hydrolysis and then to esterification with alcohol to give the compounds of the general formula (Ila).
- the hydrolysis of nitrile proceeds preferably with sodium hydroxide or potassium hydroxide in aqueous solution, and the esterification is preferably performed by refluxing in alcohol and in the presence of conc. sulfuric acid or a certain amount of a catalyst
- this reaction is conducted in an organic solvent, for example acetone, methylethylketone, diethylketone or dimethylformamide under a reaction temperature of the room temperature to the solvent refluxing temperature.
- an inorganic base for example potassium carbonate or sodium carbonate and further the addition of potassium iodide are also preferable.
- the compounds of the general formula (III) or (IV) can typically be prepared by allowing the compounds represented by the general formula (IIIa) or (IVa) to react with a mild oxidizing agent, for example m-chloroperbenzoic acid, hydrogen peroxide etc., of equimolar or excess amount in an adequate solvent, for example methylene chloride, alcohol etc. respectively.
- a mild oxidizing agent for example m-chloroperbenzoic acid, hydrogen peroxide etc.
- Example 8 the compounds listed in Table 2 were synthesized.
- Example 11 Likewise as in Example 11, the title compound was obtained as brown oil with yield of 69.0%.
- Example 14 the title compound was obtained as brown oil with overall yield of 67.3%.
- Example 16 the compounds listed in Table 3 were synthesized.
- Example 23 the compounds listed in Table 4 were synthesized.
- Example 33 the compounds listed in Table 5 were synthesized.
- Example 31 the title compound was obtained as pale yellow oil with yield of 81.0%. Analysis (%) for C 31 H 42 O 8 S, Calcd. (Found) : C, 64.78 (64.76) ; H, 7.37 (7.38).
- Example 31 the title compound was obtained as pale yellow oil with yield of 58.4%. Analysis (%) for C 31 H 42 O 9 S, Calcd. (Found) : C, 63.03 (63.14) ; H, 7.17 (7.19).
- Example 16 and 31 the compounds listed in Table 6 were synthesized.
- the compounds of the present invention displayed a strong leukotriene antagonist activity in isolated guinea pig ileum or trachea, and furthermore displayed the effect on bronchoconstriction by oral administration at low doses.
- the compounds of the present invention are useful for treatment of the diseases induced by leukotrienes, such as bronchial asthma, allergic diseases in eye, nose, stomach and intestines, allergic skin inflammation, and disorders in the circulatory system and so on.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Claims (12)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP53374/88 | 1988-03-07 | ||
JP5337488 | 1988-03-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0332109A1 EP0332109A1 (fr) | 1989-09-13 |
EP0332109B1 true EP0332109B1 (fr) | 1991-12-04 |
Family
ID=12941043
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP89103897A Expired - Lifetime EP0332109B1 (fr) | 1988-03-07 | 1989-03-06 | Dérivés d'acide phénoxyalkylcarboxylique et procédé pour leur préparation |
Country Status (9)
Country | Link |
---|---|
US (2) | US4985585A (fr) |
EP (1) | EP0332109B1 (fr) |
KR (1) | KR960007602B1 (fr) |
CN (1) | CN1022407C (fr) |
AU (1) | AU617439B2 (fr) |
CA (1) | CA1331763C (fr) |
DE (1) | DE68900485D1 (fr) |
ES (1) | ES2045219T3 (fr) |
HU (2) | HU208524B (fr) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4985585A (en) | 1988-03-07 | 1991-01-15 | Kyorin Pharmaceutical Co., Ltd. | Phenoxyalkylcarboxylic acid derivatives and process for their preparations |
US5290812A (en) * | 1991-01-18 | 1994-03-01 | Kyorin Pharmaceutical Co., Ltd. | Phenoxyalkylcarboxylic acid derivatives and process of preparing the same |
WO2001054684A1 (fr) * | 2000-01-26 | 2001-08-02 | Kyorin Pharmaceutical Co., Ltd. | Gouttes ophtalmologiques |
US7060854B2 (en) * | 2003-06-24 | 2006-06-13 | Medicinova, Inc. | Process for making polymorphic form A of 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid |
US7064146B2 (en) * | 2003-06-24 | 2006-06-20 | Medicinova, Inc. | Pharmaceutical compositions of isolated orthorhombic crystalline 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid and methods of use |
AU2005237607B2 (en) | 2004-04-27 | 2010-12-16 | Medicinova, Inc. | Phenoxyalkycarboxylic acid derivatives in the treatment of inflammatory diseases |
EP1997491B1 (fr) | 2004-07-14 | 2010-09-22 | Inflammation Research Center Company Ltd. | Procédé d'inhibition d'une métastase de tumeur |
US8962687B2 (en) | 2012-12-05 | 2015-02-24 | Medicinova, Inc. | Method of treating liver disorders |
US8835499B2 (en) | 2011-12-08 | 2014-09-16 | Medicinova, Inc. | Method of treating non-alcoholic fatty liver disease and steatohepatitis |
WO2015013395A1 (fr) | 2013-07-25 | 2015-01-29 | Medicinova, Inc. | Procédés pour réduire les niveaux de sang de triglycéride, de cholestérol total et de lipoprotéine de basse densité |
US9346754B2 (en) | 2014-05-08 | 2016-05-24 | Medicinova, Inc. | Method of treating advanced non-alcoholic steatohepatitis |
US20150321989A1 (en) | 2014-05-08 | 2015-11-12 | Medicinova, Inc. | Method of treating idiopathic pulmonary fibrosis |
JP6469727B2 (ja) | 2014-06-02 | 2019-02-13 | メディシノバ・インコーポレイテッドMediciNova, Inc. | 線維症の抑制又は治療方法 |
CA3217719A1 (fr) | 2021-05-28 | 2022-12-01 | Kazuko Matsuda | Derives d'acide phenoxyalkylcarboxylique et leur utilisation pour abaisser les taux de triglycerides |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2058785B (en) * | 1979-09-05 | 1983-05-25 | Glaxo Group Ltd | Phenol derivatives |
EP0056172B1 (fr) * | 1981-01-09 | 1985-04-03 | FISONS plc | Composés contenant les restes phénoxy et/ou thiophénoxy, méthodes pour la préparation de ces composés et compositions pharmaceutiques les contenant |
US4507498A (en) * | 1982-04-09 | 1985-03-26 | Hoffmann-La Roche Inc. | Phenoxycarboxylic acids |
IL69691A (en) * | 1982-09-23 | 1988-01-31 | Merck Frosst Canada Inc | Leukotriene antagonists,their preparation and pharmaceutical compositions containing them |
AU7450087A (en) * | 1987-05-22 | 1988-11-24 | Lunam, M.A. | Pillow |
JPH0819041B2 (ja) | 1987-09-10 | 1996-02-28 | 杏林製薬株式会社 | フェノキシアルキルカルボン酸誘導体及びその製造法 |
US4985585A (en) | 1988-03-07 | 1991-01-15 | Kyorin Pharmaceutical Co., Ltd. | Phenoxyalkylcarboxylic acid derivatives and process for their preparations |
US5290812A (en) | 1991-01-18 | 1994-03-01 | Kyorin Pharmaceutical Co., Ltd. | Phenoxyalkylcarboxylic acid derivatives and process of preparing the same |
-
1989
- 1989-02-23 US US07/313,900 patent/US4985585A/en not_active Ceased
- 1989-03-01 AU AU30884/89A patent/AU617439B2/en not_active Expired
- 1989-03-02 CA CA000592555A patent/CA1331763C/fr not_active Expired - Lifetime
- 1989-03-03 HU HU912411A patent/HU208524B/hu unknown
- 1989-03-03 HU HU891039A patent/HU204030B/hu unknown
- 1989-03-04 KR KR1019890002683A patent/KR960007602B1/ko not_active IP Right Cessation
- 1989-03-06 EP EP89103897A patent/EP0332109B1/fr not_active Expired - Lifetime
- 1989-03-06 ES ES89103897T patent/ES2045219T3/es not_active Expired - Lifetime
- 1989-03-06 DE DE8989103897T patent/DE68900485D1/de not_active Expired - Lifetime
- 1989-03-07 CN CN89101301A patent/CN1022407C/zh not_active Expired - Lifetime
-
2003
- 2003-07-21 US US10/622,589 patent/USRE38921E1/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
KR960007602B1 (ko) | 1996-06-07 |
HU208524B (en) | 1993-11-29 |
HU204030B (en) | 1991-11-28 |
US4985585A (en) | 1991-01-15 |
HU912411D0 (en) | 1991-12-30 |
AU617439B2 (en) | 1991-11-28 |
EP0332109A1 (fr) | 1989-09-13 |
CN1022407C (zh) | 1993-10-13 |
USRE38921E1 (en) | 2005-12-13 |
HUT50112A (en) | 1989-12-28 |
CN1036560A (zh) | 1989-10-25 |
DE68900485D1 (de) | 1992-01-16 |
AU3088489A (en) | 1989-09-07 |
CA1331763C (fr) | 1994-08-30 |
KR890014435A (ko) | 1989-10-23 |
ES2045219T3 (es) | 1994-01-16 |
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